Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy

Abstract

Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM.Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype.Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D′ = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08.Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM.

HLA class I and II alleles may influence susceptibility to adult dermatomyositis in a Mexican mestizo population

“…This concept is supported by reports of family groups with IIM and according to those who develop the disease after exposure to environmental agents in certain geographical areas and during certain times of the year [12].…”

“…Some studies have described alleles of the ancestral HLA haplotype (HLA-A1~B8~DRB1*03:01 ~DQA*05:01) as risk factors for multiple autoimmune diseases, conferring very high possibilities of autoimmunity without being associated with specific diseases [12].…”

Associations between TNF-α-308A/G Polymorphism and Susceptibility with Dermatomyositis: A Meta-Analysis

“…Twelve studies were excluded because they contained no extractable data, other polymorphism data or review [23]–[34]. Finally, a total of eight published documents met our inclusion criteria [10]–[17](Fig.…”

Myositis registries and biorepositories

“…Nonetheless, MSA phenotypes and some clinical subgroups have distinct HLA risk and protective factors [21,22,26,88,94,162]. Through candidate gene studies, additional immune response genes have been identified as risk factors, including PTPN22 [135], STAT4 [89], NF-kappaB [27], pro-inflammatory cytokine polymorphisms of TNFa and IL-1a [115;140], immunoglobulin heavy chain phenotypes in JDM, dermatomyositis, and polymyositis, and NOTCH4 polymorphisms in IBM [95]. A genome-wide association study [15*] that combined specimens from several registries has confirmed the HLA region as strongest region of risk, but found additional autoimmune loci to be risk factors for dermatomyositis.…”